This proposal is the continuation of an ongoing project to generate the targeted preclinical data needed to[unreadable] design and improve our current and future clinical trials in mesothelioma. Although the aims are hypothesisdriven[unreadable] and include mechanistic studies, this project will continue to be "translational" in nature. The current[unreadable] focus is on immunotherapy. Over the past threee years, the major hypothesis of this project has been that[unreadable] the success of immunotherapy can be improved by augmenting the ability of effector cells to successfully[unreadable] traffic into tumors and/or by preventing the inactivation of immune cells that do enter the tumors. This[unreadable] concept has been tested and validated in mesothelioma models using combinations of immuno-gene therapy[unreadable] with surgical debulking and with cyclooxygenase-2 (COX-2) inhibition. These ideas are being incorporated[unreadable] in the planned Phase 2 trials. In this proposal, well-characterized pre-clinical mouse[unreadable] models will be used to develop[unreadable] practical approaches that can be used to augment efficacy in immuno- and immuno-gene therapeutic trials.[unreadable] In Specific Aim 1, the optimal approaches and mechanisms of combining blockade of tumor-induced[unreadable] immunosuppresion (by inhibiting TGF-beta and COX-2) with immuno-gene and adoptive transfer therapy will[unreadable] be explored. The goal of Specific Aim 2 is to study the optimal approaches and mechanisms of combining[unreadable] gemcitabine chemotherapy with immuno-gene and adoptive transfer therapy. Specific Aim 3 will explore the[unreadable] optimal approaches and mechanisms of increasing the trafficking of immunocytes to tumors after immunogene[unreadable] and adoptive transfer therapy using agents targetting the tumor vasculature (DMXAA). Specific Aim 4[unreadable] will evaluate and improve trafficking of human anti-mesothelin T-bodies. At the[unreadable] suggestion of the reviewers, Specific Aim 5 was added to conduct experiments using patient material to assess the effects of immunotherapy and immunotherapy augmentation. Future studies will[unreadable] explore additional immuno- and immuno-gene therapy opportunities or augmenting immune therapies.[unreadable] Effective approaches will be implemented into future clinical trials conducted by the other investigators in this[unreadable] PO1. This project will thus continue to be the critical "testing ground" to allow approaches to move from[unreadable] "bench to bedside".[unreadable]